Functional coupling between the Kv1.1 channel and aldoketoreductase Kvβ1

The Shaker family voltage-dependent potassium channels (Kv1) assemble with cytosolic beta-subunits (Kv beta) to form a stable complex. All Kv beta subunits have a conserved core domain, which in one of them (Kv beta 2) is an aldoketoreductase that utilizes NADPH as a cofactor. In addition to this core, Kv beta 1 has an N terminus that closes the channel by the N-type inactivation mechanism. Point mutations in the putative catalytic site of Kv beta 1 alter the on-rate of inactivation. Whether the core of Kv beta 1 functions as an enzyme and whether its enzymatic activity affects N-type inactivation had not been explored. Here, we show that Kv beta 1 is a functional aldoketoreductase and that oxidation of the Kv beta 1-bound cofactor, either enzymatically by a substrate or non-enzymatically by hydrogen peroxide or NADP(+), induces a large increase in open channel current. The modulation is not affected by deletion of the distal C terminus of the channel, which has been suggested in structural studies to interact with Kv beta. The rate of increase in current, which reflects NADPH oxidation, is similar to 2-fold faster at 0-mV membrane potential than at similar to 100 mV. Thus, cofactor oxidation by Kv beta 1 is regulated by membrane potential, presumably via voltage-dependent structural changes in Kv1.1 channels.